chr15-98948640-C-A

Position:

• chr15-98948640-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000875.5(IGF1R):​c.3654C>A​(p.Asn1218Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1218D) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: IGF1R NM_000875.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.554

Genes affected

IGF1R (HGNC:5465): (insulin like growth factor 1 receptor) This receptor binds insulin-like growth factor with a high affinity. It has tyrosine kinase activity. The insulin-like growth factor I receptor plays a critical role in transformation events. Cleavage of the precursor generates alpha and beta subunits. It is highly overexpressed in most malignant tissues where it functions as an anti-apoptotic agent by enhancing cell survival. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, May 2014]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a domain Protein kinase (size 275) in uniprot entity IGF1R_HUMAN there are 10 pathogenic changes around while only 1 benign (91%) in NM_000875.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), IGF1R. . Trascript score misZ 4.6449 (greater than threshold 3.09). GenCC has associacion of gene with growth delay due to insulin-like growth factor I resistance.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
IGF1R	NM_000875.5	c.3654C>A	p.Asn1218Lys	missense_variant	20/21	ENST00000650285.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
IGF1R	ENST00000650285.1	c.3654C>A	p.Asn1218Lys	missense_variant	20/21		NM_000875.5	P4
IGF1R	ENST00000649865.1	c.3651C>A	p.Asn1217Lys	missense_variant	20/21			A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;.;D;.
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.41	N
LIST_S2	Pathogenic	0.98	.;.;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.90	D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.2	M;.;M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.4	.;.;D;D
REVEL	Pathogenic	0.69
Sift	Pathogenic	0.0	.;.;D;D
Sift4G	Pathogenic	0.0	.;.;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.90, 0.81
MutPred		0.88		Gain of methylation at N1218 (P = 0.0135);.;Gain of methylation at N1218 (P = 0.0135);.;
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		-0.18
Varity_R		0.94
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-99491869;